Tissue transglutaminase (TG2, EC 2.3.2.13) is a unique member of the transglutaminase family of enzymes. In addition to catalyzing Ca2+-dependent posttranslational modification of proteins by inserting irreversible ε(γ-glutamyl)lysine crosslinks between substrate proteins, it can catalyze calcium-independent hydrolysis of guanosine 5′-triphosphate (GTP), the protein disulfide isomerase reaction, and serine/threonine kinase activity. TG2's ability to hydrolyze GTP enables it to serve as a signaling molecule and activates a downstream target, phospholipase C. Although, predominantly a cytosolic protein, TG2 can also be secreted outside the cell where it regulates cell-matrix interactions; can translocate to the nucleus where it associates with pRb, p53, and histones to regulate certain cellular functions; and can be expressed on the cell membrane in association with β-integrins where it serves as a coreceptor for integrin-mediated binding to fibronectin (Fn). Cell surface TG2 can affect important cell functions such as attachment, spreading, motility, and survival.
Involvement of TG2 in apoptosis has been well established; overexpression of TG2 results in either spontaneous apoptosis of cells or rendering cells highly sensitive to apoptosis-inducing agents. In contrast with this, recent evidence indicates that increased expression of TG2 may prolong cell survival by preventing apoptosis. Several reports have documented elevated expression of TG2 in various cancer types. We and others have reported that the basal expression of TG2 in several tumor cells and tumor cell lines is elevated when they become resistant to chemotherapeutic drugs. Importantly, the increased TG2 expression was associated with an increased resistance to chemotherapeutic drugs and other apoptosis-inducing stimuli. Inhibition of TG2 by small interfering RNA (siRNA) reversed the sensitivity of drug-resistant MCF-7 breast cancer cells to doxorubicin and rendered them sensitive to serum-withdrawal-induced apoptosis. Tumor cells from metastatic sites and cell lines with metastatic potential also have been found to express high basal levels of TG2. Elevated expression of TG2 in pancreatic cancer cells has been detected by conventional methods and cDNA microarrays. These findings suggest that TG2 expression plays a role in the development of drug resistance and metastatic phenotypes in cancer cells. However, no direct link between TG2, drug resistance, and metastasis has been established, and the molecular pathways that result in constitutive expression of TG2 in cancer cells remain elusive.
Like the expression of TG2, expression of the PKCδ isoform is associated with the metastatic phenotype in some cancers. Protein kinase C (PKC) plays a central role in signal transduction pathways that mediate the action of growth factors, tumor promoters and cellular oncogenes. The tumor promoter phorbol ester results in the activation of PKC and can either promote or inhibit the growth of human pancreatic cancer cells. Similarly, phorbol ester can induce TG2 expression in various cell types. Depending on the cell type, PKCδ can function as a tumor suppressor, proapoptotic factor, or anti-apoptotic factor and can regulate cell proliferation and cell survival functions.